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TauP301L disengages from the proteosome core complex and neurogranin coincident with enhanced neuronal network excitability
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-06-18 , DOI: 10.1038/s41419-024-06815-2
Katriona L Hole 1, 2 , Bangfu Zhu 1 , Laura Huggon 1, 3 , Jon T Brown 4 , Jody M Mason 1 , Robert J Williams 1
Affiliation  

Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially tau propagation before measurable neurodegeneration is evident, but the underlying molecular events are not well defined. Human non-mutated 0N4R tau (tauWT) and P301L mutant 0N4R tau (tauP301L) were expressed in mouse primary cortical neurons using adeno-associated viruses to monitor early molecular changes and synaptic function before the onset of neuronal loss. In this model tauP301L was differentially phosphorylated relative to tauwt with a notable increase in phosphorylation at ser262. Affinity purification - mass spectrometry combined with tandem mass tagging was used to quantitatively compare the tauWT and tauP301L interactomes. This revealed an enrichment of tauP301L with ribosomal proteins but a decreased interaction with the proteasome core complex and reduced tauP301L degradation. Differences in the interaction of tauP301L with members of a key synaptic calcium-calmodulin signalling pathway were also identified, most notably, increased association with CaMKII but reduced association with calcineurin and the candidate AD biomarker neurogranin. Decreased association of neurogranin to tauP301L corresponded with the appearance of enhanced levels of extracellular neurogranin suggestive of potential release or leakage from synapses. Finally, analysis of neuronal network activity using micro-electrode arrays showed that overexpression of tauP301L promoted basal hyperexcitability coincident with these changes in the tau interactome and implicating tau in specific early alterations in synaptic function.



中文翻译:


TauP301L 从蛋白酶体核心复合物和神经颗粒蛋白中脱离,同时神经元网络兴奋性增强



tau蛋白病的特征是错误折叠的tau蛋白病理性积累。新出现的观点是,在可测量的神经变性明显之前,有毒的 tau 蛋白会导致突触功能障碍和潜在的 tau 蛋白传播,但潜在的分子事件尚未明确定义。使用腺相关病毒在小鼠原代皮质神经元中表达人类非突变 0N4R tau (tau WT ) 和 P301L 突变 0N4R tau (tau P301L ),以监测神经元损失发生前的早期分子变化和突触功能。在此模型中,tau P301L相对于 tau wt被差异磷酸化,其中 ser262 处的磷酸化显着增加。使用亲和纯化-质谱结合串联质量标记来定量比较 tau WT和 tau P301L相互作用组。这表明 tau P301L与核糖体蛋白富集,但与蛋白酶体核心复合物的相互作用减少,并且 tau P301L降解减少。还发现了 tau P301L与关键突触钙-钙调蛋白信号通路成员相互作用的差异,最显着的是,与 CaMKII 的关联增加,但与钙调神经磷酸酶和候选 AD 生物标志物神经粒蛋白的关联减少。神经颗粒蛋白与 tau P301L的关联性降低,与细胞外神经颗粒蛋白水平升高相对应,表明突触可能释放或渗漏。 最后,使用微电极阵列对神经元网络活动进行分析表明,tau P301L的过度表达促进了基础过度兴奋性,这与 tau 相互作用组的这些变化一致,并且暗示 tau 参与了突触功能的特定早期改变。

更新日期:2024-06-19
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